Multifunctional Tumor-Specific Carrier-Free Nanodrugs for Triple-Negative Breast Cancer Treatment by Combination of Chemotherapy, PTT, and Immunotherapy.

Photothermal therapy (PTT) enables rapid and efficient in situ tumor eradication, and immunogenic cell death (ICD) induced by PTT enhances immune responses at tumor sites, achieving sustained tumor suppression and preventing recurrence. However, the low photothermal conversion efficiency and tumor-targeting capability of the photothermal agents limit PTT. Additionally, the highly expressed heat shock proteins (HSPs) in tumors compromise PTT. To address these limitations, a multifunctional tumor-specific carrier-free nanodrug, IG@PDA-FA NPs, was designed for combined chemo-PTT therapy. First, IG@PDA-FA NPs demonstrated a high encapsulation efficiency of up to 81.83% for Gambogic acid (GA) and 61.13% for Indocyanine green (ICG), and enhanced tumor accumulation through the EPR effect and folate receptor-mediated targeting. Second, compared to free ICG, IG@PDA-FA NPs significantly improved photothermal conversion efficiency (PCE) from 14.50 to 21.75% by an aggregation-caused quenching (ACQ) effect. Moreover, GA in IG@PDA-FA NPs not only induced apoptosis but also enhanced the PTT efficacy through HSP downregulation. IG@PDA-FA NPs promoted tumor ICD through the chemo-PTT effect, further activating cytotoxic T cells and promoting M2-to-M1 macrophage polarization at tumor sites. Ultimately, IG@PDA-FA NPs effectively suppressed tumor growth and metastasis by a combination of chemotherapy, PTT, and immunotherapy, offering a promising strategy for triple-negative breast cancer treatment.